Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants - 27/06/14
Doi : 10.1016/j.jaci.2013.08.053
Ralf J.P. van der Valk, PhD a, b, c, ∗, Liesbeth Duijts, MD, PhD b, c, d, ∗, Nicolas J. Timpson, MD, PhD d, e, Muhammad T. Salam, MD, PhD f, Marie Standl, MSc g, John A. Curtin, PhD h, Jon Genuneit, MD, MSc i, Marjan Kerhof, MD, PhD j, Eskil Kreiner-Møller, MD k, l, Alejandro Cáceres, MD, PhD m, n, o, Anna Gref, MSc p, Liming L. Liang, MD, PhD q, r, H. Rob Taal, MD, PhD a, b, c, Emmanuelle Bouzigon, MD, PhD s, t, Florence Demenais, MD s, t, Rachel Nadif, PhD u, v, Carole Ober, PhD w, Emma E. Thompson, PhD w, Karol Estrada, PhD c, x, Albert Hofman, MD, PhD c, André G. Uitterlinden, PhD a, c, x, Cornélia van Duijn, PhD c, Fernando Rivadeneira, MD, PhD c, Xia Li, MS f, Sandrah P. Eckel, PhD f, Kiros Berhane, PhD f, W. James Gauderman, MD, PhD f, Raquel Granell, PhD d, David M. Evans, PhD d, e, Beate St Pourcain, PhD d, Wendy McArdle, PhD d, John P. Kemp, MSc d, e, George Davey Smith, MD, PhD d, e, Carla M.T. Tiesler, MSc g, Claudia Flexeder, MSc g, Angela Simpson, MD, PhD h, Clare S. Murray, MD, PhD h, Oliver Fuchs, MD, PhD y, z, Dirkje S. Postma, MD, PhD aa, bb, Klaus Bønnelykke, MD, PhD k, l, Maties Torrent, MD, PhD o, cc, Martin Andersson, MD, PhD dd, ee, Patrick Sleiman, MD, PhD ff, Hakon Hakonarson, MD, PhD ff, William O. Cookson, MD, PhD gg, Miriam F. Moffatt, PhD gg, Lavinia Paternoster, PhD d, e, Erik Melén, MD, PhD p, hh, Jordi Sunyer, MD, PhD m, n, o, ii, Hans Bisgaard, MD, DMSci k, l, Gerard H. Koppelman, MD, PhD j, aa, bb, Markus Ege, MD, PhD z, Adnan Custovic, MD, PhD h, Joachim Heinrich, PhD g, Frank D. Gilliland, MD, PhD f, Alexander J. Henderson, MD d, ‡, Vincent W.V. Jaddoe a, b, c, ‡, Johan C. de Jongste, MD, PhD b, ⁎, ‡ 
for the
for the
EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium
a Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands
b Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands
c Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
d School of Social and Community Medicine, University of Bristol (IEU), Bristol, United Kingdom
e MRC Integrative Epidemiology Unit, University of Bristol (IEU), Bristol, United Kingdom
f Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, Calif
g Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
h University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
i Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
j University Medical Center Groningen, University of Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands
k Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
l Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark
m Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
n Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
o Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Barcelona, Spain
p Institute of Environmental Medicine and Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
q Department of Epidemiology, Harvard School of Public Health, Boston, Mass
r Department of Biostatistics, Harvard School of Public Health, Boston, Mass
s Inserm, UMR 946, Genetic Variation and Human Diseases Unit, F-75010, Paris, France
t University Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, F-75007, Paris, France
u Inserm, Centre for research in Epidemiology and Population Health (CEPH), U1018, Respiratory and Environmental Epidemiology Team, F-94807, Villejuif, France
v University Paris-Sud, UMRS 1018, F-94807, Villejuif, France
w Department of Human Genetics, University of Chicago, Chicago, Ill
x Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
y Inselspital, Universitätsspital, Bern, Universitätklinik für Kinderheilkunde, Bern, Switzerland
z Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany
aa Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
bb Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
cc ib-salut, Area de Salut de Menorca, Balearic Islands, Spain
dd Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
ee Department of Physiology, South Central Hospital, Stockholm, Sweden
ff Center for Applied Genomics, Children’s Hospital of Philadelphia and Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
gg National Heart and Lung Institute, Imperial College London, London, United Kingdom
hh Sach’s Children's Hospital, Stockholm, Sweden
ii Pompeu Fabra University (UPF), Barcelona, Spain
∗Corresponding author: Johan C. de Jongste, MD, PhD, Pediatric Respiratory Medicine, Department of Pediatrics, Erasmus University Medical Center–Sophia’s Children’s Hospital, Rotterdam, The Netherlands.
Abstract |
Background |
The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes.
Objective |
We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.
Methods |
Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110).
Results |
We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10−9), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10−8) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
Conclusion |
This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
Le texte complet de cet article est disponible en PDF.Key words : Airway inflammation, asthma phenotypes, biomarker, genetics, genome-wide association study
Abbreviations used : eQTL, Feno, GCTA, GSDMB, GWA, LD, LGALS9, LYRM9, NOS, ORMDL3, SNP, ZPBP2
Plan
| C.O. is supported by a NIH grant that supported the Hutterite studies (R01 HL085197). D.E. is supported by UK Medical Research Council Centre (G0600705). G.S. is supported by UK Medical Research Council Centre (G0600705). J.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). L.D. is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community's Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 (no. MC 1226-2009). N.T. is supported by UK Medical Research Council Centre (G0600705). R.V. was partly supported by an unrestricted personal grant from GlaxoSmithKline, NL. V.J. is supported by the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). |
|
| Disclosure of potential conflict of interest: R. J. P. van der Valk has received an unrestricted personal grant from GlaxoSmithKline for partial salary payment. L. Duijts is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community's Seventh Framework Programme (FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 [no. MC 1226-2009]). M. T. Salam has received research support from the National Heart, Lung, and Blood Institute (NHLBI; 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048); the Children's Environmental Health Center funded by the National Institute of Environmental Health Sciences; and the Environmental Protection Agency (EPA; 5P01ES009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. J. A. Curtin receives royalties from UCSF irrelevant to this work for a patent related to Cancer. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25-1). S. P. Eckel has received research support from the National Institutes of Health (NIH). D. M. Evans has received a grant in the form of the MRC New Investigator Award G0600705. K. Berhane has received research support from the NIH. W. J. Gauderman has received research support from the NHLBI. B. St Pourcain has received research support with Autism Speaks (7132). A. Simpson has received grants from the Medical Research Council and Microsoft Research; is employed by the University of Manchester; has grants/grants pending from the MRC and EUFP7; receives payment for lectures, including service on speakers' bureaus from Chiesi and GlaxoSmithKline; and has received travel support from GlaxoSmithKline and Phadia for the EAACI and BSACI meetings. O. Fuchs has received research support from the European Commission within Seventh Framework Programme (theme FP7-KBBE-2007-1) as part of EFRAIM (Impact of exogenous factors in the development of Allergy, contract no. 211911), the European Respiratory Society for a long-term research fellowship (no. 675), and the Austrian, German and Swiss Pediatric Respiratory Society for a training scholarship. D. S. Postma has consultant arrangements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and TEVA; has received research support from AstraZeneca and Chiesi; and has received lecture fees from Chiesi. H. Bisgaard has received consultancy fees from Chiesi; has received travel support from the American Academy of Allergy, Asthma & Immunology (AAAAI) and the American Thoracic Society; and is a board member for Boehringer Ingelheim and Chiesi. G. H. Koppelman has received support from the Dutch Lung Foundation and BBMRI-NL. M. Ege has received research support from the European Commission and European Research Council. A. Custovic has grants/grants pending from the MRC Moulton Charitable Foundation; and has received lecture fees from GlaxoSmithKline, Thermo Fisher Scientific, Airsonet, Novartis, MSD, and ALK-Abelló. F. D. Gilliand has received research support from the NHLBI (5R01HL61768 and 5R01HL76647), Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048), the Children's Environmental Health Center funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency (5P01Es009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. A. J. Henderson has received research support from MRC (UK) and the Wellcome Trust. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2013
American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 134 - N° 1
P. 46-55 - juillet 2014 Retour au numéro
Article précédent
- Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: Meta-analysis of controlled clinical trials
- Daniel R. Morales, Brian J. Lipworth, Bruce Guthrie, Cathy Jackson, Peter T. Donnan, Virginia H. Santiago
- Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: A double-blind randomized controlled trial
- Saifudin Khalid, Robert Murdoch, Amy Newlands, Kevin Smart, Angela Kelsall, Kimberley Holt, Rachel Dockry, Ashley Woodcock, Jaclyn A. Smith
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?